The overall goal of this proposal is to apply quantitative methods for ultrasonic tissue characterization to elucidate physiologic and pathologic three-dimensional ventricular myofiber architecture and define the functional consequences of abnormal architecture at the tissue level. We will delineate fundamental mechanisms of ventricular remodeling under pathologic conditions of infarction, cardiomyopathy, and hypertension with emphasis on the potential role played by the interstitium in both systolic an diastolic dysfunction associated with these disease processes. Diverse experimental preparations of myocardial infarction (pig), heritable cardiomyopathy (Syrian hamster, tight-skin mouse), and hypertensive hypertrophy (spontaneously hypertensive rat, perinephritic dog), as well as human heart tissue obtained at autopsy from patients who suffered from these disorders will be examined with ultrasound to measure frequency- dependent backscatter and attenuation. Ultrasonic interrogation with high- frequency, high-resolution acoustic microscopy will be performed in vitro on excised samples of heart tissues and results will be compared with data acquired in vivo with a real-time two-dimensional backscatter imager described previously. Histologic and biochemical techniques will be used to quantify tissue morphometry and collagen content. Serial ultrasonic examinations will be performed to delineate the evolution of tissue structural remodeling. The sensitivity of tissue characterization for detection and monitoring of potentially beneficial effects of therapy with angiotensin-converting enzyme (ACE) inhibitors will be determined at selected stages of remodeling for each experimental model. Mathematical modeling of the fundamental scattering behavior of normal and pathologic tissues will be applied to predict abnormal regional passive elastic stiffness an diastolic dysfunction and the response of both regional and global Doppler derived diastolic parameters to therapy with ACE inhibitors. The proposed research will facilitate the development and validation of quantitative, ultrasonic criteria to detect potentially specific features of remodeling that differentiate ischemic, idiopathic, and hypertensive cardiomyopathies and to diagnose incipient heart failure in asymptomatic patients. These data also should provide a foundation for the development of a robust, clinically applicable method for characterizing regional and global diastolic dysfunction attributable to tissue architectural remodeling.